Multiparticulates are well-known dosage forms that comprise a multiplicity of particles whose totality represents the intended therapeutically useful dose of a drug. When taken orally, multiparticulates generally disperse freely in the gastrointestinal tract, maximize absorption, and minimize side effects. See, for example, Multiparticulate Oral Drug Delivery (Marcel Dekker, 1994), and Pharmaceutical Pelletization Technology (Marcel Dekker, 1989).
It is well known that some drugs are capable of existing in several different crystalline forms. A specific example of a drug that may exist in one of several crystalline forms is azithromycin, for which many different crystalline forms have been identified thus far. See commonly owned U.S. patent application Publication No. 20030162730. The most stable form of azithromycin at ambient temperature and humidity (e.g., 25° C. and 50% relative humidity) is the crystalline dihydrate, described in U.S. Pat. No. 6,268,489, which is a crystalline form that includes water.
It is known that some drug multiparticulate formulations, especially those using a lipid or glyceride-based carrier, show changes in performance upon aging under controlled conditions. See, for example, San Vicente et al., 208 Intl. J. Pharm. 13 (2000), U.S. Pat. No. 5,213,810, Jorgensen et al., 153 Intl. J. Pharm. 1 (1997), Eldem et al., 8 Pharm. Res. 47 (1991) and Eldem et al., 8 Pharm. Res. 178 (1991). The observed changes in performance are often attributed to changes in the morphology of the carrier over time, but there is no disclosure or suggestion of any method to prevent such changes in morphology.
Product literature provided by Gattefossé, makers of Gelucire® products (mixtures of fatty acid esters of glycerol and polyethylene glycol) suggest heat treatment of Gelucir®-based drug formulations filled into hard gelatin capsules. Gelucire® Technical Dossier (2d Ed 1996). However, the use of such a process for stabilization of multiparticulates is not disclosed.
Bulletin Technique Gattefossé No. 89, page 47, (1996) discloses that drug release from formulations containing Gelucire® bases may change with storage, but concedes that very little is known regarding how to prevent such changes.
U.S. Pat. Nos. 5,597,416, 5,869,098, 6,048,541, and 6,165,512 all disclose a process for crystallizing sugars in an amorphous feedstock by exposing the feedstock to a crystallization enhancer, such as ethanol. However, there is no suggestion of using such a process to stabilize a drug-containing multiparticulate.
Thus, there is a need in the art for processes for forming drug-containing multiparticulates that have improved stability. This invention addresses that need.